The general research goal is to study the therapeutic potential, and mechanisms of action, of tetracyclines(TCs) in protecting extracellular matrix(ECM) and preventing cancer metastasis. My particular interest is in TCs newly discovered ability to suppress the matrix metalloproteinases activity and to prevent angiogenesis. The long-term goal of this research is to demonstrate that TCs, including chemically modified tetracyclines (CMTs) which are devoid antimicrobial properties, can prevent pathologic ECM breakdown. We specifically propose to study the ability of a special formulated non-antimicrobial TC(CMT-3) to inhibit connective tissue breakdown in a tumor cell culture system. A complete interstitial ECM, which is well established in Dr.Simon's lab, will be employed to characterize the tumor cell-mediated ECM degradation. Our preliminary results have demonstrated that tumor proteinases (matrix metalloproteinases and one specific tumor serine proteinase, tumor-associated trypsin) both contributed to the high ECM degradative activities of a human colon carcinoma cell line, COLO 205. We then intend to use COLO 205 as a model system to study the ability and the mechanisms of CMT-3 in protecting ECM from breakdown through its inhibitory effect on tumor enzymes. The ultimate goal is to connect the effect of CMTs on this cancer cell model system to oral cancer and select one or more CMTs for use in preliminary human clinical trial.